The innate immune response is a critical component of host defense against infection. Defensins, one family of antimicrobial peptides, are an evolutionarily conserved class of innate immune effectors with well-described anti-bacterial activity; however, their role in anti-viral immunity is less well understood. The potent neutralization of diverse viruses by alpha-defensins has been described in vitro and in cell culture. Recent studies have also described enhancement of virus infection by alpha-defensins; however, controlled studies to determine whether these peptides impact virus infection and pathogenesis in vivo have not been reported. This proposal will explore the hypothesis that alpha-defensins modulate enteric non-enveloped virus infection and pathogenesis in vivo, using replicating viruses in a natural host. We will determine the spectrum of activity of mouse enteric alpha-defensins against mouse enteric viruses in vitro. Using this information, we will determine whether alpha-defensin expression directly or indirectly impacts enteric virus infection and pathogenesis in vivo. We will also determine whether host Paneth cells respond to virus infection by degranulating and releasing alpha-defensins into the gut. These studies will provide insight into a critical component of the immune system that may be a common first line of defense against many viral pathogens. In addition, a deeper understanding of enteric virus infection will aid in the design of vaccine vectors to elicit mucosal immunity. Finally, these studies will provide validation for continued studies of the antiviral mechanisms of defensins as well as the development of these molecules as therapeutics for adenovirus and other viral pathogens.